Pulsatile secretion of the islet hormones at an interval of 10-14 minutes has now been demonstrated conclusively in several species including man. The proposed work will utilize insights gained from in vitro studies performed in our laboratory in an effort to comprehensively assess the impact of pulsatile insulin secretion in the whole animal. The long term objective is to devise better insulin treatment strategies for human diabetics based on studies of pulsatile insulin administration to nonhuman primates. Work will proceed in three sequential stages each of which addresses a separate specific aim. First, the importance of pulsatile insulin secretion in normal physiology will be assessed by comparing the effects of continuous portal insulin replacement with those of pulsatile portal replacement at the natural secretory interval. Responses studied will include hepatic glucose production, glucose clearance, ketogenesis, lipolysis, glucose counterregulation, and entrainment of glucagon secretion. Second, the consequences of varying the interval at which insulin pulses are administered peripherally will be examined. Previous in vitro work has suggested that differences in the frequency responsiveness of peripheral and hepatic tissues might be exploited to enhance the hepatic effects of peripherally- administered insulin. Finally, the efficacy of long term continuous and pulsatile insulin replacement in streptozotocin diabetic primates will be compared. The frequency of pulsatile insulin administration found in the second phase of this work to optimize hepatic responses will be used in these treatment trials. In future proposals the understanding gained in primates will be implemented with programmable hormone infusion technology to evaluate the efficacy of pulsatile insulin therapy of human diabetics.